Epidemiological studies have shown that at least 62% of cocaine abusers and possibly up to 90% in some populations are concomitant alcohol abusers. We conducted a study which investigated the effects of simultaneous consumption of cocaine and alcohol in humans and prospectively demonstrated the formation of cocaethylene, a metabolite formed by ethyl esterification of cocaine which appears to have pharmacological properties similar to cocaine. Subjects experienced prolonged and increased euphoria relative to cocaine or alcohol alone administration and had significant increases in heart rate following cocaine-alcohol administration leading to speculation regarding the role of cocaethylene. Our pilot study in which intranasal cocaethylene was administered to 8 subjects showed it to be similar to cocaine, but with an elimination half-life about twice that of cocaine. our pilot study of acute disulfiram 250 mg treatment followed by cocaine administration showed decreased cocaine craving and increased dysphoria in some subjects. In our open pilot study, outpatients randomized to disulfiram 250 mg daily had a significant decrease in cocaine use as compared to subjects treated with naltrexone. This FIRST application is composed of a series of pharmacologic challenge (study drug administration) studies designed to test the hypothesis that cocaethylene plays a significant role in behavioral and physiological responses during cocaine- alcohol abuse. The 5 proposed studies will each enroll 28 subjects for a total of 140 subjects over 5 years. The studies have been designed to include an analysis of gender differences in responses to study drug administration which may be important to the pathoetiology of cocaine- alcohol abuse and could have important implications for treatment. Study 1 will explore the effects of multiple doses of cocaine in the presence of a steady state of ethanol. Studies 2 and 3 will determine the behavioral, physiological and pharmacokinetic properties of cocaethylene in humans using cocaine as a comparator. Studies 4A and 4B will test the hypothesis that disulfiram is an efficacious pharmacotherapy for cocaine and alcohol abuse using a double-blind, placebo-controlled, limited randomization, dose-response study design. Cocaethylene has been shown to have mush greater selectivity for the dopamine transporter than does cocaine and does not block serotonin reuptake. One hypothesis regarding the high incidence of comorbid cocaine and alcohol abuse is that cocaethylene, with its lack of serotonin reuptake inhibition, alleviates acute abstinence symptoms and dysphoria associated with binge cocaine use. Cocaethylene may be used as a tool to sort out the role of serotonin versus dopamine in mediating the actions of disulfiram on cocaine effects. Cocaethylene will be utilized in Study 4B as a pharmacologic probe in an attempt to deuterium the relative contribution of dopamine and serotonin to cocaine effects and to develop an understanding of possible mechanisms by which disulfiram modifies drug effects. Findings from this study could be important to the development of new pharmacotherapies for cocaine-alcohol abuse. In total, these studies should provide significant contributions to the current state of knowledge regarding the epidemiology of cocaine-alcohol abuse and treatment of these disorders.